Chromosome abnormalities are often associated with genetic disorders, degenerative diseases, and cancer. In particular, the deletion or multiplication of copies of whole chromosomes or chromosomal segments, and higher level amplifications of specific regions of the genome are common occurrences in cancer. See, for example Smith (1991) Breast Cancer Res. Treat., 18: Suppl. 1: 5–14; van de Viler (1991) Became. Beefiest. Acta. 1072: 33–50, Sato (1990) Cancer. Res., 50: 7184–7189. In fact, the amplification of DNA sequences containing proto-oncogenes and the deletion of DNA sequences containing tumor-suppressor genes, are each frequently characteristic of tumorigenesis. Dutrillaux (1990) Cancer Genet. Cytogenet. 49: 203–217.
Mutation of the p53 gene is the most common genetic alteration in human cancers (Bartek (1991) Oncogene 6: 1699–1703, Hollstein (1991) Science, 253: 49–53). Moreover, introduction of wild-type p53 in mammalian cancer cells lacking endogenous wild-type p53 protein suppresses the neoplastic phenotype of those cells (see, e.g., U.S. Pat. No. 5,532,220).
Of the many available chemotherapeutic drugs, paclitaxel, available commercially as TAXOL® (NSC number: 125973) has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6:17–23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134–146, Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247–1259). Recent studies on the interaction of paclitaxel and tumor suppressor gene therapy show that reduced levels of tumor suppressor (i.e., p53) correlated with increased G2/M phase arrest, micronucleation, and p53 independent paclitaxel-induced apoptosis. In contrast, surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21Cipl,wafl protein levels (Wahl (1996) Nature Med. 2:72–79). Similarly, Hawkins (1996) Canc. Res. 56: 892–898, showed that inactivation of p53 enhanced sensitivity to certain antimitotic agents including paclitaxel. The authors suggested that p53 may play a role in DNA repair, thereby allowing cells to progress more readily through S phase even in the presence of drugs. These studies thus suggest that tumor suppressor gene therapy and drug therapy with anti-mitotic agents (especially paclitaxel therapy) act at cross purposes.